Feasibility and diagnostic benefit of increased cerebrospinal fluid volume and frequency in the diagnosis of tuberculous meningitis

Abstract

Background: Definite diagnosis of tuberculous meningitis (TBM) requires demonstration of TB bacilli in the cerebrospinal fluid (CSF) on smear, culture, or nucleic acid amplification. However, the sensitivity of these tests is low. This study was done to see if smear and culture done on a larger volume and repeated samples of CSF increases the diagnostic yield of these tests. Methods: Adult patients with clinical features of meningitis for >5 days were prospectively and consecutively recruited. At admission, the usual 1 ml of CSF was taken for mycobacterial testing; another 4–8 ml was also taken for the same as the comparison. On the 3rd hospital day, 4–8 ml of CSF was taken for mycobacterial testing. Mycobacterial smear and culture were done by Auramine O stains and on modified Lowenstein–Jensen medium, respectively. The composite reference standard for TBM was considered the gold standard for the diagnosis of TBM. Definite and probable diagnosis was taken as positive, while a possible diagnosis and no TB were considered negative for TBM. In a subset, Xpert MTB/Rif assay was also performed on the CSF samples as per the routine diagnostic protocol. Results: 66/80 (82.5%) had the initial CSF examination in the emergency department, 80 (100%) had large-volume CSF on day 1, while 22/80 (27.5%) consented for the second large-volume CSF examination on day 3. There was a marginal increase in sensitivity from 22% to 26% with increasing CSF volume from 1 ml to 4–8 ml and 36% if another large-volume CSF was collected at 72 h. The specificity was 100% at all times. The negative likelihood ratios were 0.78, 0.74, and 0.64, respectively. The sensitivity of Xpert MTB/RI compared to the composite reference standard of TBM was 30.4%. Conclusions: Increasing the volume and frequency of CSF testing for Mycobacterium tuberculosis, marginally improves the sensitivity and negative likelihood ratios, but may not be adequate to rule out TBM with the certainty required to withhold antitubercular therapy. The feasibility of repeat CSF examinations needs to be considered while making guidelines.